The goal of this proposal is to elucidate the role of dendritic Ca2+ spikes in learning-dependent synaptic plasticity in the mouse cortex. Dendritic Ca2+ spikes enhance the computational power of individual neurons by amplifying synchronously activated excitatory synaptic inputs. In vitro studies have shown that dendritic Ca2+ spikes play an important role in activity-dependent synaptic potentiation and depression. The in vivo function of dendritic Ca2+ spikes in synaptic plasticity remains elusive. Our preliminary studies show that different motor learning tasks induce dendritic Ca2+ spikes on different apical tuft branches of layer V (L5) pyramidal neurons in the mouse primary motor cortex. We propose to investigate how such task-and branch-specific dendritic Ca2+ spikes affect the induction and maintenance of synaptic plasticity in the motor cortex. With a combination of experimental approaches including in vivo two-photon imaging and pharmacogenetic manipulations of neuronal activity, we will determine how dendritic Ca2+ spikes cause synaptic potentiation and depotentiation on different apical branches of individual L5 pyramidal neurons in response to different motor learning tasks. We will also investigate whether dendritic Ca2+ spikes promote branch-specific formation of new dendritic spines and whether newly-formed spines are co-active with adjacent spines in a task-specific manner. Our preliminary studies indicate that inactivation of somatostatin-expressing interneurons disrupts branch-specific generation of Ca2+ spikes. We will further investigate if such disruption affects the induction and maintenance of synaptic plasticity during motor learning. In addition, we will examine how the activity of somatostatin- expressing interneurons, the generation of branch-specific Ca2+ spikes and dendritic spine plasticity are altered in a mouse model of Fragile X syndrome. The proposed experiments will reveal the fundamental role of branch-specific dendritic Ca2+ spikes in the induction and maintenance of synaptic plasticity during learning and memory formation. These studies will also provide novel insights into developing new strategies for the treatment of intellectual disability and autism.